Monitoring therapy response of experimental arthritis with radiolabeled tracers targeting fibroblasts, macrophages or integrin $alpha$v$beta$3.

S. Terry, M. Koenders, G. Franssen, T. Nayak, A. Freimoser-Grundschober, C. Klein, W. Oyen, O. Boerman and P. Laverman




Rheumatoid arthritis is an autoimmune disease resulting in chronic synovial inflammation. Molecular imaging could be used to monitor therapy response, thus enabling tailored therapy regimens and enhancing therapeutic outcome. Here, we hypothesized that response to etanercept could be monitored by radionuclide imaging in arthritic mice. We tested three different targets namely fibroblast activation protein (FAP), macrophages, and integrin ?v?3.Male DBA/1J mice with collagen-induced arthritis were treated with etanercept. SPECT/CT (Single photon emission computed tomography/ X-ray computed tomography) scans were acquired at 1, 24 and 48 h after injecting (111)In-RGD2 (integrin ?v?3), (111)In-anti-F4/80-A3-1 (anti-murine macrophage antibody), or (111)In-28H1 (anti-FAP antibody), respectively, with nonspecific controls included. Mice were dissected after the last scan and scans were analyzed quantitatively and were correlated with macroscopic scoring.Experimental arthritis was imaged with (111)In-28H1 (anti-FAP), (111)In-anti-F4/80-A3-1, and (111)In-RGD2. Tracer uptake in joints correlated with arthritis score. Treatment decreased joint uptake of tracers; it decreased from 23�15 \%ID/g, 8�4 \%ID/g, 2�1 \%ID/g to 11�11 \%ID/g (p<0.001), 4�4 \%ID/g (p<0.001), 1�0.2 \%ID/g (p<0.01) for (111)In-28H1, (111)In-anti-F4/80-A3-1, and (111)In-RGD2, respectively. Arthritis-to-blood ratios (in mice with arthritis score 2 per joint) were higher for (111)In-28H1 (5.5�1; excluding values over 25), (111)In-anti-F4/80-A3-1 (10.4�4), and (111)In-RGD2 (7.2�1) than for control (111)In-DP47GS (0.7�0.5; P = 0.002), (111)In-rat IgG2b (0.5�0.2; P = 0.002), or coinjection of excess RGD2, (3.5), indicating specific uptake of all tracers in arthritic joints.(111)In-28H1, (111)In-anti-F4/80-A3-1, and (111)In-RGD2 can be used to specifically monitor the response to therapy in experimental arthritis at the molecular level. Further studies however still need to be carried out.

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